Efficient Replication by Herpes Simplex Virus Type 1 Involves Activation of the IκB Kinase-IκB-p65 Pathway

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Abstract
Infection by herpes simplex virus type 1 (HSV-1) induces a persistent nuclear translocation of NFκB. To identify upstream effectors of NFκB and their effect on virus replication, we employed mouse embryo fibroblast (MEF)-derived cell lines with deletions of either IKK1 or IKK2, the catalytic subunits of the IκB kinase (IKK) complex. Infected MEFs were assayed for virus yield, loss of IκBα, nuclear translocation of p65, and NFκB DNA-binding activity. Absence of either IKK1 or IKK2 resulted in an 86 to 94% loss of virus yield compared to that of normal MEFs, little or no loss of IκBα, and greatly reduced NFκB nuclear translocation. Consistent with reduced virus yield, accumulation of the late proteins VP16 and gC was severely depressed. Infection of normal MEFs, Hep2, or A549 cells with an adenovirus vector expressing a dominant-negative (DN) IκBα, followed by superinfection with HSV, resulted in a 98% drop in virus yield. These results indicate that the IKK-IκB-p65 pathway activates NFκB after virus infection. Analysis of NFκB activation and virus replication in control and double-stranded RNA-activated protein kinase-null MEFs indicated that this kinase plays no role in the NFκB activation pathway. Finally, in cells where NFκB was blocked because of DNIκB expression, HSV failed to suppress two markers of apoptosis, cell surface Annexin V staining and PARP cleavage. These results support a model in which activation of NFκB promotes efficient replication by HSV, at least in part by suppressing a host innate response to virus infection.